CN102356078B - 制备烯胺羰基化合物的新方法 - Google Patents
制备烯胺羰基化合物的新方法 Download PDFInfo
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- CN102356078B CN102356078B CN201080012432.4A CN201080012432A CN102356078B CN 102356078 B CN102356078 B CN 102356078B CN 201080012432 A CN201080012432 A CN 201080012432A CN 102356078 B CN102356078 B CN 102356078B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 36
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 43
- -1 methoxy ethyl Chemical group 0.000 claims description 37
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 14
- 150000001412 amines Chemical class 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000007848 Bronsted acid Substances 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 3
- ZNOVTXRBGFNYRX-UHFFFAOYSA-N 2-[[4-[(2-amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-UHFFFAOYSA-N 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- 229940117389 dichlorobenzene Drugs 0.000 claims description 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 3
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 abstract description 6
- 239000002585 base Substances 0.000 description 59
- 229910052731 fluorine Inorganic materials 0.000 description 20
- 239000011737 fluorine Substances 0.000 description 20
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 16
- 229910052801 chlorine Inorganic materials 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 14
- 150000001728 carbonyl compounds Chemical class 0.000 description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 12
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 11
- 125000001188 haloalkyl group Chemical group 0.000 description 11
- PEQJBOMPGWYIRO-UHFFFAOYSA-N n-ethyl-3,4-dimethoxyaniline Chemical compound CCNC1=CC=C(OC)C(OC)=C1 PEQJBOMPGWYIRO-UHFFFAOYSA-N 0.000 description 11
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 10
- 125000000753 cycloalkyl group Chemical group 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000003710 aryl alkyl group Chemical group 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical group 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 239000011630 iodine Substances 0.000 description 6
- 125000002769 thiazolinyl group Chemical group 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- 125000000262 haloalkenyl group Chemical group 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 3
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 2
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 2
- FEWLNYSYJNLUOO-UHFFFAOYSA-N 1-Piperidinecarboxaldehyde Chemical compound O=CN1CCCCC1 FEWLNYSYJNLUOO-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- SZNYYWIUQFZLLT-UHFFFAOYSA-N 2-methyl-1-(2-methylpropoxy)propane Chemical compound CC(C)COCC(C)C SZNYYWIUQFZLLT-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 210000005252 bulbus oculi Anatomy 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- LDHQCZJRKDOVOX-NSCUHMNNSA-M crotonate Chemical compound C\C=C\C([O-])=O LDHQCZJRKDOVOX-NSCUHMNNSA-M 0.000 description 2
- QRVSDVDFJFKYKA-UHFFFAOYSA-N dipropan-2-yl propanedioate Chemical compound CC(C)OC(=O)CC(=O)OC(C)C QRVSDVDFJFKYKA-UHFFFAOYSA-N 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 150000002240 furans Chemical class 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 230000000749 insecticidal effect Effects 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000009666 routine test Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical class C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- SEQRDAAUNCRFIT-UHFFFAOYSA-N 1,1-dichlorobutane Chemical compound CCCC(Cl)Cl SEQRDAAUNCRFIT-UHFFFAOYSA-N 0.000 description 1
- RELMFMZEBKVZJC-UHFFFAOYSA-N 1,2,3-trichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1Cl RELMFMZEBKVZJC-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- KNKRKFALVUDBJE-UHFFFAOYSA-N 1,2-dichloropropane Chemical compound CC(Cl)CCl KNKRKFALVUDBJE-UHFFFAOYSA-N 0.000 description 1
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 description 1
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical compound C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 description 1
- LOWMYOWHQMKBTM-UHFFFAOYSA-N 1-butylsulfinylbutane Chemical class CCCCS(=O)CCCC LOWMYOWHQMKBTM-UHFFFAOYSA-N 0.000 description 1
- AIDFJGKWTOULTC-UHFFFAOYSA-N 1-butylsulfonylbutane Chemical compound CCCCS(=O)(=O)CCCC AIDFJGKWTOULTC-UHFFFAOYSA-N 0.000 description 1
- BFCFYVKQTRLZHA-UHFFFAOYSA-N 1-chloro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Cl BFCFYVKQTRLZHA-UHFFFAOYSA-N 0.000 description 1
- NVJUHMXYKCUMQA-UHFFFAOYSA-N 1-ethoxypropane Chemical compound CCCOCC NVJUHMXYKCUMQA-UHFFFAOYSA-N 0.000 description 1
- NJAKRNRJVHIIDT-UHFFFAOYSA-N 1-ethylsulfonyl-2-methylpropane Chemical compound CCS(=O)(=O)CC(C)C NJAKRNRJVHIIDT-UHFFFAOYSA-N 0.000 description 1
- MBDUIEKYVPVZJH-UHFFFAOYSA-N 1-ethylsulfonylethane Chemical compound CCS(=O)(=O)CC MBDUIEKYVPVZJH-UHFFFAOYSA-N 0.000 description 1
- URDYJNJREUFXGD-UHFFFAOYSA-N 1-ethylsulfonylpropane Chemical compound CCCS(=O)(=O)CC URDYJNJREUFXGD-UHFFFAOYSA-N 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- YBJCDTIWNDBNTM-UHFFFAOYSA-N 1-methylsulfonylethane Chemical compound CCS(C)(=O)=O YBJCDTIWNDBNTM-UHFFFAOYSA-N 0.000 description 1
- JSZOAYXJRCEYSX-UHFFFAOYSA-N 1-nitropropane Chemical compound CCC[N+]([O-])=O JSZOAYXJRCEYSX-UHFFFAOYSA-N 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- BQCCJWMQESHLIT-UHFFFAOYSA-N 1-propylsulfinylpropane Chemical class CCCS(=O)CCC BQCCJWMQESHLIT-UHFFFAOYSA-N 0.000 description 1
- JEXYCADTAFPULN-UHFFFAOYSA-N 1-propylsulfonylpropane Chemical compound CCCS(=O)(=O)CCC JEXYCADTAFPULN-UHFFFAOYSA-N 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- MCDJZKPTBCWNSJ-UHFFFAOYSA-N 2-methyl-1-(2-methylpropylsulfinyl)propane Chemical class CC(C)CS(=O)CC(C)C MCDJZKPTBCWNSJ-UHFFFAOYSA-N 0.000 description 1
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- PLAZTCDQAHEYBI-UHFFFAOYSA-N 2-nitrotoluene Chemical compound CC1=CC=CC=C1[N+]([O-])=O PLAZTCDQAHEYBI-UHFFFAOYSA-N 0.000 description 1
- RMSSLCSOZKTRDB-UHFFFAOYSA-N 3-(methylamino)-2h-furan-5-one Chemical compound CNC1=CC(=O)OC1 RMSSLCSOZKTRDB-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- WBUOVKBZJOIOAE-UHFFFAOYSA-N 3-chlorobenzonitrile Chemical compound ClC1=CC=CC(C#N)=C1 WBUOVKBZJOIOAE-UHFFFAOYSA-N 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- WXYDKGMJJFFORR-UHFFFAOYSA-N 3-methyl-1-(3-methylbutylsulfinyl)butane Chemical class CC(C)CCS(=O)CCC(C)C WXYDKGMJJFFORR-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- PNWSHHILERSSLF-UHFFFAOYSA-N 4-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC=C(C(O)=O)C=C1C(O)=O PNWSHHILERSSLF-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- ZNSMNVMLTJELDZ-UHFFFAOYSA-N Bis(2-chloroethyl)ether Chemical compound ClCCOCCCl ZNSMNVMLTJELDZ-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- BNXYVROGIGSJNK-UHFFFAOYSA-N C(C=1C(C(=O)OCCCCCCCC)=CC=CC1)(=O)OCCCCCCCC.C#C Chemical compound C(C=1C(C(=O)OCCCCCCCC)=CC=CC1)(=O)OCCCCCCCC.C#C BNXYVROGIGSJNK-UHFFFAOYSA-N 0.000 description 1
- 0 Cc1cc(*)c(*)nc1 Chemical compound Cc1cc(*)c(*)nc1 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- AQZGPSLYZOOYQP-UHFFFAOYSA-N Diisoamyl ether Chemical compound CC(C)CCOCCC(C)C AQZGPSLYZOOYQP-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
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- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
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- BNIXVQGCZULYKV-UHFFFAOYSA-N pentachloroethane Chemical compound ClC(Cl)C(Cl)(Cl)Cl BNIXVQGCZULYKV-UHFFFAOYSA-N 0.000 description 1
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- 229920000570 polyether Polymers 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
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- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical class O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
- A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
- A01N43/08—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with oxygen as the ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/62—Three oxygen atoms, e.g. ascorbic acid
Abstract
本发明涉及一种制备烯胺羰基化合物的方法，在所述方法中，使式(II)化合物与式(III)化合物在布忍司特酸存在下进行反应，其中，基团A、R1、R2和Z的定义如说明书所述；
Description
技术领域
本发明涉及一种制备烯胺羰基化合物的方法。
背景技术
一些特殊的取代烯胺羰基化合物作为杀虫活性化合物公布于EP 0 539 588A1。此外，国际专利申请WO2007/115644、WO2007/115643和WO2007/115646也描述了相应的杀虫活性的烯胺羰基化合物。
通常，烯胺羰基化合物根据下面的路线1由特窗酸和一种胺合成。该方法描述于例如EP 0 539 588Al和杂环化合物(Heterocycles)，27卷，8，1907-1923页(1988)中。
路线1：
该方法的一个特定的缺陷在于需要用无水特窗酸作起始化合物，而无水特窗酸的制备不方便且费用昂贵。
例如，特窗酸通常由乙酰乙酸乙酯通过溴化然后进行氢化而制备(参见，合成通讯(Synthetic Communication)，11(5)，385-390页(1981))。以乙酰乙酸乙酯为原料的特窗酸的总收率低于40％，这使得该方法从工业角度看不是非常有吸引力。
瑞士专利503 722描述了另一种制备特窗酸的方法。在该方法中，使4-氯乙酰乙酸乙酯与一种芳香胺反应得到3-芳基氨基巴豆酰内酯，然后通过用无机酸处理而释放出特窗酸。该方法的缺陷是特窗酸的分离仅可通过高真空升华进行，这也使得该方法从工业角度看不是非常有吸引力。
另一种制备特窗酸的方法描述于EP 0 153 615A中，其由2，4-二氯乙酰乙酸酯起始反应。这同样是多级且复杂的方法，同样仅能得到65％中等总收率的所需化合物。
四面体快报(Tetrahedron Letters)，第31期，2683和2684页(1974)描述了特窗酸和一种相应烯胺羰基化合物的制备。其中描述的合成在下面的路线2中再现。所用的反应物是乙炔二甲酸二甲酯。
路线2：
该方法的缺陷是仅为30％的较低总收率，以及必须使用昂贵反应物例如氢化铝锂(LiAlH4)作试剂。
在现有技术中还公开了一种由乙酰乙酸甲酯起始来制备烯胺羰基化合物的方法(杂环化学杂志(J.Heterocyclic Chem.)，21，1753(1984))。对于该方法，所用的原料是昂贵的4-溴-3-甲氧基丁-3-烯羧酸酯。
另一种方法由一种4-氯乙酰乙酸酯开始，其与胺反应(杂环化合物，Vol.27，No.8，1988，1907-1923页)。得到氨基呋喃的反应在一个步骤中进行。这包括将胺与冰醋酸加入到4-氯乙酰乙酸乙酯的苯溶液中，并将得到的混合物加热回流几小时。该合成方法中4-甲基氨基-2(5H)-呋喃酮的收率仅为40％。
EP 0 123 095A公开了一种由3-氨基-4-乙酰氧基巴豆酸酯制备特窗酰胺(tetronamide)的方法。3-氨基-4-乙酰氧基巴豆酸酯昂贵且制备不方便，所以用此方法无法进行经济上可行的合成。
另一种由丙二酸酯和氯乙酰氯制备特窗酸的方法从J.Chem.Soc.，Perkin Trans.1(1972)，9/10，1225-1231页中可知。该方法得到产率仅为43％的所需目标化合物。
WO 2007/115644描述了烯胺羰基化合物的制备，例如通过使4-[[(6-氯吡啶-3-基)甲基]氨基]呋喃-2(5H)-酮和3-溴-1，1-二氯丙-1-烯反应制备4-[[(6-氯吡啶-3-基)甲基](3，3-二氯丙-2-烯-1-基)氨基]呋喃-2(5H)-酮(见制备实施例，方法2，实施例(3))。WO 2007/115644也描述了烯胺羰基化合物的制备，例如通过4-[[(2-氟乙基)氨基]呋喃-2(5H)-酮和2-氯-5-氯甲基吡啶反应制备4-[[(6-氯吡啶-3-基)甲基](2-氟乙基)氨基]呋喃-2(5H)-酮(见制备实施例，方法3，实施例(4))。所述反应优选用锂或钠的氢化物进行。这些底物通常昂贵，同时出于安全原因而难以处理。
在要求欧洲专利申请07116639优先权的WO 2009/036899中，制备了烯胺羰基化合物，例如由4-(甲氧羰基)-5-氧-2，5-二氢呋喃-3-醇和胺进行制备。
路线3：
其中，
R1为氢、烷基、卤代烷基、烯基、卤代烯基、炔基、环烷基、环烷基烷基、卤代环烷基、烷氧基、烷氧基烷基、卤代环烷基烷基或芳基烷基；
Z为氢、碱金属或碱土金属；且
A为6-位任选被氟、氯、溴、甲基、三氟甲基或三氟甲氧基取代的吡啶-2-基或吡啶-4-基、或吡啶-3-基，或为6-位任选被氯或甲基取代的哒嗪-3-基，或为2-位任选被氯或甲基取代的吡嗪-3-基或2-氯吡嗪-5-基或1，3-噻唑-5-基，或为任选被氟、氯、溴、氰基、硝基、任选被氟和/或氯取代的C1-C4-烷基、任选被氟和/或氯取代的C1-C3-烷硫基、任选被氟和/或氯取代的C1-C3-烷基磺酰基取代的嘧啶基、吡唑基、噻吩基、噁唑基、异噁唑基、1，2，4-噁二唑基、异噻唑基、1，2，4-三唑基或1，2，5-噻二唑基，或为
其中
X为卤素、烷基或卤代烷基，且
Y为卤素、烷基、卤代烷基、卤代烷氧基、叠氮基或氰基。
发明内容
从该现有技术出发，本发明一个目的是提供一种优选实施简单且便宜的制备烯胺羰基化合物的替代方法。通过该期望的方法可获得的烯胺羰基化合物应优选以高收率和高纯度获得。更具体地，该期望的方法应使得所需目标化合物无需复杂的纯化步骤即可获得。
该目的通过一种制备通式(I)的烯胺羰基化合物的新方法实现：
本发明方法的特征在于，将通式(II)的化合物
与通式(III)的胺反应
其中各个基团定义如下：
R1为氢、烷基、卤代烷基、烯基、卤代烯基、炔基、环烷基、环烷基烷基、卤代环烷基、烷氧基、烷氧基烷基、卤代环烷基烷基或芳基烷基；
R2为烷基、卤代烷基、烯基、卤代烯基、炔基、环烷基、环烷基烷基、卤代环烷基、烷氧基烷基、卤代环烷基烷基、芳基或芳基烷基；
Z选自(C＝O)OR3和(C＝O)NR1CH2A，其中R3选自C1-12-烷基、C3-8-环烷基、C2-12-烯基、C2-12-炔基、C6-8-芳基、C7-19-芳基烷基或C7-19-烷基芳基，其各自可被一种或多种选自-R’、-OR’、-SR’、-NR’2、-SiR’3、-COOR’、-(C＝O)R’、-CN和-CONR2’的基团取代，其中R’为氢或C1-12-烷基；
A为6-位任选被氟、氯、溴、甲基、三氟甲基或三氟甲氧基取代的吡啶-2-基或吡啶-4-基、或吡啶-3-基，或为6-位任选被氯或甲基取代的哒嗪-3-基，或为2-位任选被氯或甲基取代的吡嗪-3-基或2-氯吡嗪-5-基或1，3-噻唑-5-基，或为
任选被氟、氯、溴、氰基、硝基、任选被氟和/或氯取代的C1-C4-烷基、任选被氟和/或氯取代的C1-C3-烷硫基、任选被氟和/或氯取代的C1-C3-烷基磺酰基取代的嘧啶基、吡唑基、噻吩基、噁唑基、异噁唑基、1，2，4-噁二唑基、异噻唑基、1，2，4-三唑基或1，2，5-噻二唑基，或为
其中
X为卤素、烷基或卤代烷基，且
Y为卤素、烷基、卤代烷基、卤代烷氧基、叠氮基或氰基。
本发明由此设想通过使式(II)的相应化合物与式(III)的胺进行反应而制备所需的式(I)的烯胺羰基化合物。所需的式(I)的烯胺羰基化合物在下面详细给出的反应条件下以良好收率和高纯度获得，这意味着本发明方法克服了已知方法的缺陷。所需化合物以通常不必对直接反应产物进行大量后处理的纯度获得。
上述通式(I)和(III)中所示的A和R1基团的优选、特别优选和更特别优选的定义给出如下。
A优选选自下组：6-氟吡啶-3-基、6-氯吡啶-3-基、6-溴吡啶-3-基、6-甲基吡啶-3-基、6-三氟甲基吡啶-3-基、6-三氟甲氧基吡啶-3-基、6-氯-1，4-哒嗪-3-基、6-甲基-1，4-哒嗪-3-基、2-氯-1，3-噻唑-5-基或2-甲基-1，3-噻唑-5-基、2-氯嘧啶-5-基、2-三氟甲基嘧啶-5-基、5，6-二氟吡啶-3-基、5-氯-6-氟吡啶-3-基、5-溴-6-氟吡啶-3-基、5-碘-6-氟吡啶-3-基、5-氟-6-氯吡啶-3-基、5，6-二氯吡啶-3-基、5-溴-6-氯吡啶-3-基、5-碘-6-氯吡啶-3-基、5-氟-6-溴吡啶-3-基、5-氯-6-溴吡啶-3-基、5，6-二溴吡啶-3-基、5-氟-6-碘吡啶-3-基、5-氯-6-碘吡啶-3-基、5-溴-6-碘吡啶-3-基、5-甲基-6-氟吡啶-3-基、5-甲基-6-氯吡啶-3-基、5-甲基-6-溴吡啶-3-基、5-甲基-6-碘吡啶-3-基、5-二氟甲基-6-氟吡啶-3-基、5-二氟甲基-6-氯吡啶-3-基、5-二氟甲基-6-溴吡啶-3-基和5-二氟甲基-6-碘吡啶-3-基。
R1优选选自下组：氢、烷基、卤代烷基、烯基、卤代烯基、炔基、环烷基、环烷基烷基、卤代环烷基、卤代环烷基烷基和烷氧基烷基。
A更优选选自下组：6-氟吡啶-3-基、6-氯吡啶-3-基、6-溴吡啶-3-基、6-氯-1，4-哒嗪-3-基、2-氯-1，3-噻唑-5-基、2-氯嘧啶-5-基、5-氟-6-氯吡啶-3-基、5，6-二氯吡啶-3-基、5-溴-6-氯吡啶-3-基、5-氟-6-溴吡啶-3-基、5-氯-6-溴吡啶-3-基、5，6-二溴吡啶-3-基、5-甲基-6-氯吡啶-3-基、5-氯-6-碘吡啶-3-基和5-二氟甲基-6-氯吡啶-3-基。
R1更优选选自下组：甲基、乙基、正丙基、异丙基、乙烯基、烯丙基、炔丙基、环丙基、烷氧基烷基、2-氟乙基、2，2-二氟乙基和2-氟环丙基。
A最优选选自下组：6-氯吡啶-3-基、6-溴吡啶-3-基、6-氯-1，4-哒嗪-3-基、2-氯-1，3-噻唑-5-基、5-氟-6-氯吡啶-3-基和5-氟-6-溴吡啶-3-基。
R1最优选选自下组：甲基、乙基、正丙基、异丙基、正丙-2-烯基、正丙-2-炔基、环丙基、甲氧基乙基、2-氟乙基和2，2-二氟乙基。
上述式(II)中所示的Z和R2基团的优选、特别优选和更特别优选的定义给出如下。
Z优选选自(C＝O)OR3，其中R3选自C1-12-烷基、C3-8-环烷基、C2-12-烯基、C2-12-炔基、C6-8-芳基、C7-19-芳基烷基或C7-19-烷基芳基，其各自可被一种或多种选自-R’、-OR’、-SR’，其中R’为氢或C1-12-烷基的基团取代；
R2优选选自下组：烷基、卤代烷基、烯基、卤代烯基、环烷基、烷氧基烷基或芳基烷基。
Z更优选选自(C＝O)OR3，其中R3选自甲基、乙基、正丙基、异丙基或丁基；
R2更优选选自C1-C12-烷基。
Z最优选选自(C＝O)OR3，其中R3选自甲基和乙基；
R2最优选选自乙基、异丙基和丁基。
在本发明的一个优选的实施方案中，式(II)和(III)的起始化合物用于本发明方法中，其中取代基A、Z、R1、R2和R3各自具有上述优选定义，可以将优选、特别优选和更特别优选定义的取代基进行结合。
在本发明的一个特别优选的实施方案中，式(II)和(III)的起始化合物用于本发明方法中，其中取代基A、Z、R1、R2和R3各自具有上述特别优选定义，可以组合优选、特别优选和更特别优选定义的取代基。
在本发明的一个更特别优选的实施方案中，式(II)和(III)的起始化合物用于本发明方法中，其中取代基A、Z、R1、R2和R3各自具有上述更特别优选定义，可以组合优选、特别优选和更特别优选定义的取代基。
在本申请的上下文中，除非另有说明，术语“烷基”，无论单独地或与其它术语结合，例如卤代烷基、烷氧基烷基、环烷基烷基、卤代环烷基烷基和芳基烷基，应理解为是指具有1至12个碳原子且可以是带支链的或不带支链的饱和的脂肪族烃基。C1-C12-烷基的实例有甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、1-甲基丁基、2-甲基丁基、1-乙基丙基、1，2-二甲基丙基、己基、正庚基、正辛基、正壬基、正癸基、正十一烷基和正十二烷基。在这些烷基中，C1-C6-烷基是特别优选的。尤其优选的是C1-C4-烷基，尤其是甲基和乙基。
根据本发明，除非另有说明，术语“烯基”，无论单独地或与其它术语结合，应理解为是指含有至少一个双键的直链或支链C1-C12-烯基，例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1，3-丁二烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1，3-戊二烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基和1，4-己二烯基。其中，优选C2-C6-烯基，特别优选C2-C4-烯基。
根据本发明，除非另有说明，术语“炔基”，无论单独地或与其它术语结合，应理解为是指含有至少一个三键的直链或支链C2-C12-炔基，例如乙炔基、1-丙炔基和炔丙基。其中，优选C3-C6-炔基，特别优选C3-C4-炔基。该炔基也可含有至少一个双键。
根据本发明，除非另有说明，术语“环烷基”，无论单独地或与其它术语结合，应理解为是指C3-C8-环烷基，例如环丙基、环丁基、环戊基、环己基、环庚基和环辛基。其中，优选C3-C6-环烷基。
根据本发明，除非另有说明，术语“芳基”，无论单独地或与其它术语结合，应理解为是指具有6至14个碳原子的芳香族基团，优选苯基。
除非另有说明，术语“芳基烷基”应理解为是指本发明定义的“芳基”和“烷基”的结合，其中所述基团通常通过烷基连接。其实例有苄基、苯乙基或α-甲基苄基，特别优选苄基。
除非另有说明，术语“卤素取代的基团”例如卤代烷基，应理解为是指单或多卤代直至最大可能数量取代基的基团。在多卤代的情况下，卤素原子可以是相同的或不同的。卤素为氟、氯、溴或碘，尤其是氟、氯或溴。
除非另有说明，术语“烷氧基”，无论单独地或与其它术语结合，例如卤代烷氧基，在本文上下文中应理解为是指一种O-烷基，其中术语“烷基”如上述定义。
任选取代的基团可以被单取代或多取代，在多取代的情况下取代基可以是相同的或不同的。
通式(II)化合物中至少部分在现有技术中是已知的(R.Anschütz，化学学报(Chemische Berichte)，1912，45，2374；E.Benary，化学学报(Chemische Berichte)，1912，45，3682；Kuo，Sheng Chut等，杂环化学杂志(Journal of Heterocyclic Chemistry)，1989，26(3)，605-8)或可类似地制备。
本发明还提供式(II)的化合物
其中，Z和R2基团各自如上述所定义，条件是R2不为乙基或苯基。
本发明还提供根据下述路线4，合成相应的式(II)化合物的改性衍生物的方法，例如在碱存在下，用氯乙酰氯由式(IV)的丙二酸衍生物起始制备：
路线4：
其中Z和R2各自如上述所定义。
用作反应物的通式(IV)的丙二酸酯可市售获得，或可通过现有技术已知的方法制备。
本发明反应所需的通式(III)的胺可市售获得，或可通过文献方法制备(参见例如S.Patai“氨基化学(The Chemistry of AminoGroup)”、Interscience Publishers，纽约，1968)。
式(II)的化合物与式(III)的胺的反应可以在溶剂(稀释剂)的存在下进行。溶剂以反应混合物在全过程中保持易于搅拌的量使用较为有利。可用于实施本发明方法的溶剂包括在反应条件下呈惰性的所有有机溶剂。
所述溶剂的实例包括：卤代烃类，尤其是氯代烃，例如四氯乙烯、四氯乙烷、二氯丙烷、二氯甲烷、二氯丁烷、氯仿、四氯化碳、三氯乙烷、三氯乙烯、五氯乙烷、二氟苯、1，2-二氯乙烷、氯苯、溴苯、二氯苯、氯甲苯、三氯苯；醚类，例如乙基丙基醚、甲基叔丁基醚、正丁基醚、苯甲醚、苯乙醚、环己基甲基醚、二甲醚、二乙醚、乙二醇二甲醚(dimethylglycol)、二苯醚、二丙醚、二异丙醚、二正丁醚、二异丁醚、二异戊醚、乙二醇二甲醚、异丙基乙基醚、甲基叔丁基醚、四氢呋喃、甲基四氢呋喃、二噁烷、二氯二乙醚；甲基-THF和环氧乙烷和/或环氧丙烷的聚醚；硝基烃类，硝基甲烷、硝基乙烷、硝基丙烷、硝基苯、氯代硝基苯、邻硝基甲苯；腈类，例如乙腈、甲腈、丙腈、丁腈、异丁腈、苄腈、苯腈、间氯苄腈以及如下化合物，例如四氢噻吩砜和二甲亚砜、四亚甲基亚砜、二丙亚砜、苄基甲基亚砜、二异丁基亚砜、二丁基亚砜、二异戊基亚砜；砜类，例如二甲砜、二乙砜、二丙砜、二丁砜、二苯砜、二己砜、甲基乙基砜、乙基丙基砜、乙基异丁基砜和五亚甲基砜；脂肪族、脂环族或芳香族烃，例如戊烷、己烷、庚烷、辛烷、壬烷；例如，包括沸点在例如40℃～250℃范围的组分的所谓石油溶剂、伞花烃、沸程在70℃～190℃的石油馏分、环己烷、甲基环己烷、石油醚、轻石油、辛烷、苯、甲苯、二甲苯；酯类，例如乙酸甲酯、乙酸乙酯、乙酸丁酯、乙酸异丁酯和碳酸二甲酯、碳酸二丁酯或碳酸亚乙酯；酰胺类，如六亚甲基磷酰胺、甲酰胺、N，N-二甲基乙酰胺、N-甲基甲酰胺、N，N-二甲基甲酰胺、N，N-二丙基甲酰胺、N，N-二丁基甲酰胺、N-甲基吡咯烷、N-甲基己内酰胺、1，3-二甲基-3，4，5，6-四氢-2(1H)嘧啶、辛基吡咯烷酮、辛基己内酰胺、1，3-二甲基-2-咪唑啉二酮、N-甲酰哌啶、N，N′-1，4-二甲酰哌嗪；和脂族醇类，如甲醇、乙醇、正丙醇和异丙醇和正丁醇。
本发明的反应优选在选自下组的溶剂中进行：二噁烷、丁睛、丙睛、乙睛、DME、甲苯、甲基-THF、二氯苯、氯苯、正庚烷、异丁醇、正丁醇、乙醇、甲基叔丁基醚、异丙基乙基醚和它们的混合物。
任选地，根据具体的起始化合物，也可进行本体反应，即不加溶剂。
本发明还可在有水存在下反应。
式(II)化合物与式(III)的胺的反应优选在布忍司特酸(acid)存在下进行。
布忍司特酸和式(III)的胺的摩尔比可改变。布忍司特酸和式(III)的胺之比优选为约10∶0.6～约1∶1.5，特别为约5∶0.9～1∶1.2，更特别为约2∶1～约1∶1.1。
可使用有机或者无机布忍司特酸。优选使用无机酸，例如磷酸(H3PO4)、硫酸(H2SO4)、盐酸(HCl)、氢溴酸(HBr)、氢氟酸((HF)或硫酸氢钾(KHSO4)。各种酸可以无水形式或者以含水形式使用，例如以85％磷酸或37％盐酸形式，即更特别地以其中所述酸的市售获得形式。合适的有机酸实例有三氟乙酸、乙酸、甲磺酸和对甲苯磺酸。在上述酸中，尤其优选磷酸、硫酸、硫酸氢钾和三氟乙酸。
制备式(I)化合物的反应通常可在减压、标准压强和加压下进行。同样，所用的温度可根据所用的底物变化，且易于本领域的技术人员通过常规试验确定。例如，制备通式(I)化合物的反应可以在20～200℃，优选20-150℃的温度下进行。
所用的式(II)和(III)的起始化合物的化学计量可以在较宽范围内变化，且通常不受任何特定限制。所用的式(II)和(III)的起始化合物的合适化学计量可以由本领域技术人员通过常规试验容易地确定。例如，所用的通式(II)的化合物与通式(III)的胺的摩尔比可以为，例如0.5～10，特别是1～6，尤其是1.05～2。原则上使用更大量的式(III)化合物也是可行的，但由于经济原因是不利的。
在反应结束时，反应的水可通过蒸馏一部分溶剂而以共沸混合物形式除去。在高沸点溶剂的情况下，其可在减压下进行。借助于该操作，通常可实现定量转化。
如果所述反应在溶剂中进行，可以在反应结束后通过蒸馏除去溶剂。这可在标准压力或减压下，在室温或升温下进行。
所需的式(I)化合物也可例如通过结晶分离。
具体实施方式
本发明通过下述实施例进行详细说明，但所述实施例不应解释为限制本发明。
制备实施例
实施例1：4-[[(6-氯吡啶-3-基)甲基](2，2-二氟乙基)氨基]呋喃
-2(5H)-酮的制备
在室温下，向于705ml丁腈中的46g2-乙氧基-4，5-二氢-4-氧代呋喃-3-甲酸乙酯和39.3g N-[(6-氯吡啶-3-基)甲基]-2，2-二氟乙胺悬浮液中加入31.2g硫酸氢钾。将混合物加热回流5小时。接着，将所述混合物冷却至室温，用890ml水进行洗涤。减压去除溶剂。得到51g4-[[(6-氯吡啶-3-基)甲基](2，2-二氟乙基)氨基]呋喃-2(5H)-酮(相当于93％的收率)。
1H NMR(CDCl3，298K)δ：3.53(td，2H)，4.52(s，2H)，4.82(s，2H)，4.83(s，1H)，5.96(tt，1H)，7.37(d，1H)，7.55(dd，1H)，8.27(d，1H)
实施例2：2-异丙氧基-4，5-二氢-4-氧代呋喃-3-甲酸异丙酯的制
备
最开始，将20g丙二酸二异丙酯加入到173g甲苯中。接着，室温下分批加入12g叔丁醇钾。2小时后，减压去除溶剂，用173g甲苯再次进行混合。0℃下，滴加6g氯乙酰氯，将反应混合物在室温下进行搅拌。接着，加入50g冰和100ml水，将混合物搅拌10分钟。去除有机相，用硫酸镁干燥。去除溶剂后，获得1∶1的2-异丙基-4，5-二氢-4-氧代呋喃-3-甲酸异丙酯(45％产率)和丙二酸二异丙酯的混合物。该混合物可进而用于下一步骤。通过柱层析，分离2-异丙氧基-4，5-二氢-4-氧代呋喃-3-甲酸异丙酯。
1H NMR(CDCl3，298K)δ：1.3d(6H)，1.50d(6H)，4.63s(2H)，5.14m(1H)，5.29m(1H)，8.56s(1H)，8.75d(1H)
实施例3：4-[[(6-氯吡啶-3-基)甲基](2，2-二氟乙基)氨基]呋喃
-2(5H)-酮的制备
室温下，向于15.8g丁腈中的1.0g 2-异丙氧基-4，5-二氢-4-氧代呋喃-3-甲酸异丙酯和0.85g N-[(6-氯吡啶-3-基)甲基]-2，2-二氟乙胺悬浮液中加入0.6g硫酸氢钾。将混合物加热回流5小时。接着，将所述混合物冷却至室温，用10ml水进行洗涤。减压去除溶剂。得到1g4-[[(6-氯吡啶-3-基)甲基](2，2-二氟乙基)氨基]呋喃-2(5H)-酮(相当于95％的产率)。
1H NMR(CDCl3，298K)δ：3.53(td，2H)，4.52(s，2H)，4.82(s，2H)，4.83(s，1H)，5.96(tt，1H)，7.37(d，1H)，7.55(dd，1H)，8.27(d，1H)
Claims (6)
1.制备式(I)化合物的方法，其特征在于，使式(II)化合物与式(III)的胺在布忍司特酸存在下进行反应；
其中
A为6-氯吡啶-3-基、6-溴吡啶-3-基、6-氯-1,4-哒嗪-3-基、2-氯-1,3-噻唑-5-基、5-氟-6-氯吡啶-3-基或5-氟-6-溴吡啶-3-基；
R1为甲基、乙基、正丙基、异丙基、正丙-2-烯基、正丙-2炔基、环丙基、甲氧基乙基、2-氟乙基或2,2-二氟乙基；
Z为-CO2CH2CH3或-CO2CH3；且
R2为乙基、异丙基或丁基。
2.根据权利要求1所述的方法，其特征在于，所述的布忍司特酸选自H3PO4、H2SO4、HCl、HBr、HF、KHSO4、三氟乙酸、乙酸、甲磺酸和对甲苯磺酸。
3.根据权利要求1或2所述的方法，其特征在于，所述反应在选自下述的溶剂中进行：二噁烷、丁腈、丙腈、乙腈、DME、甲苯、甲基-THF、二氯苯、氯苯、正庚烷、异丁醇、正丁醇、乙醇、甲基叔丁基醚、异丙基乙基醚和它们的混合物。
4.根据权利要求1或2所述的方法，其特征在于，所述反应在20℃～150℃的温度范围进行。
5.根据权利要求1或2所述的方法，其特征在于，式(II)的化合物和式(III)的化合物的摩尔比为1～6。
6.式(II)的化合物
其中Z和R2基各自如权利要求1所定义，条件为R2不为乙基。
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| PCT/EP2010/001568 WO2010105772A1 (de) | 2009-03-16 | 2010-03-12 | Neues verfahren zur herstellung von enaminocarbonyl-verbindungen |
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| EP0539588A1 (en) * | 1990-07-05 | 1993-05-05 | Nippon Soda Co., Ltd. | Amine derivative |
| WO2007115644A1 (de) * | 2006-03-31 | 2007-10-18 | Bayer Cropscience Ag | Substituierte enaminocarbonylverbindungen |
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| CH503722A (de) | 1969-05-28 | 1971-02-28 | Lonza Ag | Verfahren zur Herstellung von Tetronsäure |
| DE3311003A1 (de) | 1983-03-25 | 1984-09-27 | Bayer Ag, 5090 Leverkusen | Chromon- und thiochromonsubstituierte 1,4-dihydropyridinlactone, mehrere verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln |
| CH658056A5 (de) | 1984-02-09 | 1986-10-15 | Lonza Ag | Verfahren zur herstellung von tetronsaeure. |
| DE102004047922A1 (de) * | 2004-10-01 | 2006-04-06 | Bayer Cropscience Ag | Wirkstoffe für die Saatgutbehandlung |
| DE102006015470A1 (de) | 2006-03-31 | 2007-10-04 | Bayer Cropscience Ag | Substituierte Enaminocarbonylverbindungen |
| DE102006015468A1 (de) | 2006-03-31 | 2007-10-04 | Bayer Cropscience Ag | Substituierte Enaminocarbonylverbindungen |
| EP2042496A1 (de) | 2007-09-18 | 2009-04-01 | Bayer CropScience AG | Verfahren zur Herstellung von 4-Aminobut-2-enoliden |
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| EP0539588A1 (en) * | 1990-07-05 | 1993-05-05 | Nippon Soda Co., Ltd. | Amine derivative |
| WO2007115644A1 (de) * | 2006-03-31 | 2007-10-18 | Bayer Cropscience Ag | Substituierte enaminocarbonylverbindungen |
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| EP2230236A1 (de) | 2010-09-22 |
| BRPI1009383A8 (pt) | 2016-09-27 |
| US20120004416A1 (en) | 2012-01-05 |
| JP5732034B2 (ja) | 2015-06-10 |
| WO2010105772A1 (de) | 2010-09-23 |
| BRPI1009383B1 (pt) | 2017-02-14 |
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| WO2010105772A8 (de) | 2011-10-13 |
| KR20110133488A (ko) | 2011-12-12 |
| US8680286B2 (en) | 2014-03-25 |
| KR101652734B1 (ko) | 2016-08-31 |
| CN102356078A (zh) | 2012-02-15 |
| BRPI1009383A2 (pt) | 2015-09-01 |
| MX2011009731A (es) | 2011-09-29 |
| JP2012520334A (ja) | 2012-09-06 |
| EP2408764A1 (de) | 2012-01-25 |
| ES2428336T3 (es) | 2013-11-07 |
| TW201036954A (en) | 2010-10-16 |
| TWI491597B (zh) | 2015-07-11 |
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